| Toll-like receptors (TLR) are pathogen-recognition receptors (PRR) shown to play an important role in the innate immune system in response to pathogen associated molecular patterns (PAMPS) of bacteria, as well as other pathogens. Bacterial vaginosis (BV), an alteration in the normal flora of the female genital tract, is associated with increased risk of acquiring sexually transmitted diseases (STD) and increased seroprevalence of human cytomegalovirus (HCMV) infection. We investigated the role of TLR in the cellular response to genital tract secretions from women with BV and the effect of known TLR ligands on HCMV infection in cell culture and ectocervical explants.;We show that the presence of Trichomonas vaginalis and BV in the female genital tract are associated with a factor/s in genital tract secretions that induce(s) mouse TNF-alpha (mTNF-alpha)production by a TLR4-dependent mechanism, and this effect was not due to the presence of lipopolysaccharide (LPS, a TLR4 ligand). We also demonstrate that LPS and genital tract secretions from women with BV share the ability to up-regulate the expression of Human Immunodeficiency Virus Type I (HIV-1) in chronically infected monocytic and T-cell lines. Finally, we asked what effect the presence of TLR ligands have on subsequent infection of the female genital tract with HCMV. We found that TLR3 and TLR4, but not TLR2, activation induced resistance to HCMV infection in human foreskin fibroblasts (HFF). Our results also suggested that TLR9 activation results in a transient resistance to HCMV infection. In contrast, TLR2, TLR3, TLR4, and TLR9 activation induced resistance to HCMV infection in ectocervical explant tissues (EET). Resistance to HMCV in both HFF and EET was mediated by the production of Interferon-beta (IFN-beta), induced by TLR activation.;In summary, these results show that the presence of abnormal flora in the female genital tract is associated with the presence of a factor(s) that signal through TLR4 and that activation of TLR2, TLR3, TLR4, and TLR9 in HFF and/or EET induces resistance to HCMV infection in an IFN-beta-dependent manner. Together, these results suggest mechanisms by which the presence of TLR ligands in the genital tract may influence the epidemiology of STD. |
